The long term goal of this project is to elucidate the role of thiocyanate in human health. Thiocyanate is one of the components of the human salivary peroxidase system. Salivary peroxidase catalyzes the peroxidation of thiocyanate to hypothiocyanite which is a normal component of human saliva and inhibits the growth and metabolism of many species of oral bacteria. In vivo, the salivary peroxidase system may be in a state of dynamic equilibrium which maximizes the level of hypothiocyanite and minimizes the accumulation of toxic hydrogen peroxide. Preliminary studies from our laboratory indicate that there are pH dependent critical threshold concentrations for thiocyanate below which there is an increasing risk of hydrogen peroxide accumulation toxic for host tissues. The presence of thiocyanate also protects host cells from toxic hypochlorite generated in vivo by myeloperoxidase and/or eosinophil peroxidase-catalyzed reactions. In a thiocyanate and chloride mixture, the peroxidation product is hypothiocyanite even when chloride is in excess, indicating that thiocyanate is the preferred substrate for mammalian peroxidases. Reduction in thiocyanate could lead to a reduction of hypothiocyanite and an increase in hydrogen peroxide and in hypochlorite with resulting damage of host cells. There is some evidence suggesting this. Chemotherapy drastically reduces the thiocyanate concentration in saliva of leukemia patients. They suffer from a variety of oral lesions which may be an indirect result of reduction in thiocyanate concentration. The mechanism by which thiocyanate is reduced is not known, and based on earlier studies we hypothesize the following mechanisms for the decrease in thiocyanate concentration in saliva: 1) antineoplastic drugs negatively affect salivary gland function, thus, impairing the transport of thiocyanate from serum to saliva and 2) antineoplastic drugs impair the formation of thiocyanate by affecting the detoxification of cyanide and by their effect on the enzyme thiosulfate:cyanide sulfurtransferase. Although we are proposing two hypotheses, the specific aim of the present application is to test the second hypothesis which will probe different aspects of the overall concept. The reason for not addressing the first hypothesis at present is lack of suitable salivary gland cell lines to perform adequate transport studies. In the present study, we will determine the effects of chemotherapeutic agents on thiocyanate metabolism using guinea pigs as experimental animals.